ALDH1A3

Chr 15AR

aldehyde dehydrogenase 1 family member A3

Also known as: ALDH1A6, ALDH6, MCOP8, RALDH3

NCBI Gene: 220ENSG00000184254UniProt: P47895

This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Primary Disease Associations & Inheritance

Microphthalmia, isolated 8MIM #615113
AR
274
ClinVar variants
103
Pathogenic / LP
0.14
pLI score
0
Active trials
Clinical Summary— ALDH1A3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
103 Pathogenic / Likely Pathogenic· 61 VUS of 274 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.51LOEUF
pLI 0.141
Z-score 3.31
OE 0.26 (0.14–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.24Z-score
OE missense 0.64 (0.57–0.72)
192 obs / 301.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.14–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.57–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 6 / 23.2Missense obs/exp: 192 / 301.2Syn Z: 0.07

ClinVar Variant Classifications

274 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic86
Likely Pathogenic17
VUS61
Likely Benign58
Benign37
Conflicting4
86
Pathogenic
17
Likely Pathogenic
61
VUS
58
Likely Benign
37
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
5
75
0
86
Likely Pathogenic
1
9
7
0
17
VUS
1
39
21
0
61
Likely Benign
0
3
23
32
58
Benign
0
1
31
5
37
Conflicting
—4
Total85715737263

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ALDH1A3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ALDH1A3-related anophthalmia/microphthalmia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Microphthalmia, isolated 8

MIM #615113

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension.
Li D et al.·Circulation
2021
ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription.
Gorodetska I et al.·Theranostics
2024
Intrapancreatic adipocytes and beta cell dedifferentiation in human type 2 diabetes.
Zhang N et al.·Diabetologia
2025
Cancer-associated fibroblast heterogeneity is associated with organ-specific metastasis in pancreatic ductal adenocarcinoma.
Pan X et al.·J Hematol Oncol
2021
ALDH Enzymes and Hematological Diseases: A Scoping Review of Literature.
Foucault A et al.·Discov Med
2024Review
Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia.
Kesim Y et al.·Eur J Hum Genet
2023
ALDH1A3 is the switch that determines the balance of ALDH(+) and CD24(-)CD44(+) cancer stem cells, EMT-MET, and glucose metabolism in breast cancer.
Fernando W et al.·Oncogene
2024
ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma.
Li G et al.·Cell Death Dis
2018
Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes.
Samson JM et al.·Chem Biol Interact
2019
High expression of PKCλ and ALDH1A3 indicates a poor prognosis, and PKCλ is required for the asymmetric cell division of ALDH1A3-positive cancer stem cells in PDAC.
Kasai T et al.·Biochem Biophys Res Commun
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Co-expression of PKCζ and ALDH1A3 Is Associated With Poor Chemotherapeutic Responses in Basal-like Breast Cancer.
Nagashima Y et al.·Cancer Genomics Proteomics
2026
Dioscin Suppresses Ovarian and Gastric Tumor Progression by Inhibiting ALDH1A3-Mediated Retinoic Acid Metabolism and Cancer Stemness.
Wu K et al.·Phytother Res
2026
Dysregulation of the ALDH1A3/PML-RARα axis promotes the progression of acute promyelocytic leukemia.
Cai J et al.·Cancer Lett
2026
Proteomics analysis of human mesenchymal stromal/stem cell sarcomagenesis model identifies ALDH1A3 and CD99 as potential targets in the transformation process.
Gobin JM et al.·BMC Biol
2026🔓 Open AccessFunctional
HERVH-derived eRNA activates a super-enhancer-driven ALDH1A3/SAT1 axis to promote ferroptosis escape and pancreatic cancer development.
Yuan L et al.·Sci Adv
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools